University of Toledo’s Dr. Saurabh Chattopadhyay Secures $2.2m to Pinpoint how IRF3 Regulates Viral-Induced Inflammation

University of Toledo’s Dr. Saurabh Chattopadhyay Secures $2.2m to Pinpoint how IRF3 Regulates Viral-Induced Inflammation

Dr. Saurabh Chattopadhyay at University of Toledo recently received a five-year grant worth $2.2 million from the National Institutes of Health (NIH) to support the research center’s investigation into how a protein key to activating the body’s antiviral immune system might also regulate virus-induced inflammatory responses. This represents a revolutionary paradigm—part of the movement in research involving the harnessing of the patient’s own immune system to fight off bad pathogens. In the age of COVID-19, it’s a virus that’s wreaked havoc on the world’s human population. Imagine a future where the immune system itself could be trained to actively seek out and destroy SARS-CoV-2 or any other pathogens! But pulling this off is incredibly difficult, representing a frontier in biomedical research. After all, when it comes to the body’s immune response to a virus, too much of an effort can lead to bad results and too little a response can allow the virus to replicate out of control. This critically important research, now funded for five years, could literally lead to paradigm-shifting clinical trials in humanity’s continuous war with viral pathogens.

In a recent University of Toledo website entry, TrialSite introduces Dr. Saurabh Chattopadhyay and his investigation into the IRF3 protein and how it may play a vital role in activating the body’s antiviral immune system, while representing a key foundation for new biomedical approaches to regulating virus-induced inflammatory responses.

What is IRF3?

Called Interferon regulatory factor 3 or IRF3, this protein is a member of the interferon regulatory transcription factor (IRF) family. It was first discovered as a homolog or IRF1 and IRF2 as described in Wikipedia.  

This protein is present in most of the human body’s cells but it lays dormant until activated by infection, which rapidly induces a number of other antiviral proteins to go to work. Hence the importance of truly understanding this protein in the context of virus and other inflammatory conditions.

This protein has been further described and evidenced to possess several functional domains, including a nuclear export signal, a DNA-binding domain, a C—terminal IRF association domain and several regulatory phosphorylation sites

The protein is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This translocates into the nucleus for the transcriptional activation of interferons alpha and beta, and additional interferon-induced genes. 

This protein serves an important function in the innate immune system’s response to viral infection.

What is the core research hypothesis here?

Well Dr. Chattopadhyay shared in this University of Toledo-based news that the common wisdom has been that the actual “pathogen load determines the outcome” of the viral infection, such as influenza or the coronavirus.  However, researchers are now pursuing the role of what’s known as induced inflammatory response and its role in viral infection. The University of Toledo virologists declared recently that this immune-response may also play “…a very critical role in determining whether the virus is going to win or the host is going to win. Although inflammatory responses contribute to blocking the viral infection, too much inflammatory protein is bad for the host.”

What does this mean in more layperson’s terms?

It means that the University of Toledo researcher is investigating how to use protein-based pathway manipulation to induce just enough inflammatory response to fight and destroy a virus while not activating too much response that risks hurting the patient.

What is Dr. Chattopadhyay’s core focus of this study?

He will center research on pinpointing in more granular detail the process of how IRF3 regulates viral-induced inflammation.

Why is this particular research effort important?

Because with a superior understanding of how IRF3 regulates viral-induced inflammation it becomes more possible to target that particular pathway with therapeutics (drugs) that could minimize inflammation and hence potentially reduce the severity of viral diseases.

Can this pathway be targeted for other diseases?

Absolutely yes. The research targeted pathway could be targeted therapeutically against other diseases that are not viral in nature, for example liver inflammation.

What are implications for not being able to control inflammation?

Well, as the University of Toledo explains, the overheated immune response in humans can be devastating from a healthcare perspective. This exaggerated immune response outcome—uncontrolled inflammation can lead to the body actually attacking itself and this of course leads to dangerous conditions associated with viral infections, from influenza to the grave “cytokine storms” associated with SARS-CoV-2, the virus behind COVID-19 complications. This can be a matter of life and death.

Is Dr. Chattopadhyay a key expert in this field?

Yes. He has spent a majority of his professional career studying IRF3.

What research has led to this point?

Dr. Chattopadhyay and team back in 2016 conducted breakthrough research that evidenced the role of IRF3 contributing to the prevention of a virus from replicating in the body by inducing a pathway to selectively kill induvial virally infected cells. Put in more simplistic terms, the team found that this protein could trigger an immune response from the body to defend itself from a virus.

What’s the translational research potential here?

Well Dr. Chattopadhyay went on the record that this particular “multifaceted molecule” shows real promise. Already, he shared that he and team have “..used a drug screen of FDA-approved therapeutics to look at leveraging the cell-death pathway to fight infections.” 

Dr. Chattopadhyay believes that they can take a similar approach now to “…target the new function of IRF3 in order to regulate the inflammatory response.”

How does University of Toledo partner with industry on breakthroughs?

The University of Toledo maintains a commercialization policy and, importantly, a Technology Transfer and Commercialization office with a standard set of contract templates for review. The contact there is Stephen Snider, Associate Vice President Technology Transfer & Associate General Counsel.

Lead Research/Investigator

Saurabh Chattopadhyay, PhD, Assistant Professor, Virology